Multiple Structures for Virtual Ligand Screening: Defining Binding Site Properties-Based Criteria to Optimize the Selection of the Query
Multiple Structures for Virtual Ligand Screening: Defining Binding Site Properties-Based Criteria to Optimize the Selection of the Query
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DOI：
10.1021/ci3004557
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发表时间：
2013-02-01
影响因子：
5.6
通讯作者：
Montes, Matthieu
中科院分区：
文献类型：
--
作者：
Ben Nasr, Nesrine;Guillemain, Helene;Montes, Matthieu
基于结构的虚拟配体筛选(SBVLS)方法被广泛应用于药物发现项目中。当目标的几种结构可用时，可以使用基于单一结构对接或基于整体对接的协议。这些方法的性能取决于作为参考的结构(S)，其选择需要对耗费额外资源的基准数据库进行追溯丰富研究。在本研究中，无论使用何种对接程序(Surflex-DOCK或ICM)，我们都发现了导致在回溯性SBVLS测试中获得最佳性能的结构结合部位属性的几个趋势。通过评估它们的疏水性以及比较它们的体积和开度，我们表明，选择最佳结构应该是可能的，而不需要先前的回溯性浓缩研究。如果平均结合位体积低于350A(3)，则应首选体积较小的结构。在其他情况下，应优先选择结合位点最大的结构。可以为单结构对接策略或整体对接策略选择这些最优结构。当建造一个整体时，除了体积之外，场地的开放可能是一个有趣的标准，因为最封闭的结构在大型系统中不应该是首选的。当靶标的几种结构可用时，这些基于结合部位属性的指南可能有助于优化未来的预期药物发现方案。
Structure based virtual ligand screening (SBVLS) methods are widely used in drug discovery programs. When several structures of the target are available, protocols based either on single structure docking or on ensemble docking can be used. The performance of the methods depends on the structure(s) used as a reference, whose choice requires retrospective enrichment studies on benchmarking databases which consume additional resources. In the present study, we have identified several trends in the properties of the binding sites of the structures that led to the optimal performance in retrospective SBVLS tests whatever the docking program used (Surflex-dock or ICM). By assessing their hydrophobicity and comparing their volume and opening, we show that the selection of optimal structures should be possible with no requirement of prior retrospective enrichment studies. If the mean binding site volume is lower than 350 A(3), the structure with the smaller volume should be preferred. In the other cases, the structure with the largest binding site should be preferred. These optimal structures may be either selected for a single structure docking strategy or an ensemble docking strategy. When constructing an ensemble, the opening of the site might be an interesting criterion additionaly to its volume as the most closed structures should not be preferred in the large systems. These "binding site properties-based" guidelines could be helpful to optimize future prospective drug discovery protocols when several structures of the target are available.